BACKGROUND: Although the antinociceptive effect of high-velocity, low amplitude thrust manipulation (HVLAM) has been recognized by numerous systematic reviews, the underlying mechanism for manipulation-related pain relief remains poorly understood. An increasing number of studies have explored its analgesic mechanism suggesting that the excitation of the descending inhibitory pain mechanism (DIPM) might play the most important role for musculoskeletal pain relief. OBJECTIVE: The objective of this review is to investigate the role of the DIPM in musculoskeletal pain following HVLAM as well as to identify the pain-relieving importance of this technique within clinical practice. METHODOLOGY: English literature databases were searched to find studies related to the objective of the present review. RESULTS AND CONCLUSIONS: Findings from current literature support that HVLAM has a profound influence on nociceptive stimulus via the possible activation of the DIPM. It seems that the application of this technique activates the periaqueductal gray region area of the midbrain, stimulates the noradrenergic descending system and at the level of the spinal cord, the nociceptive afferent barrage is reduced and mechanical hypoalgesia is induced. However, the literature on HVLAM induced-analgesia is still problematic regarding the methodological design of the existing research. Despite these limitations, the clinical importance of the activation of the DIPM should not be ignored since the resulted analgesic effect of this technique can provide a window of opportunity to restore impaired physical performance and disability.